Drug microparticles

ABSTRACT

Provided are microparticles of active pharmaceutical ingredients, drug delivery vehicles comprising same, and methods for making them.

RELATED APPLICATIONS

This is a divisional patent application of U.S. patent application Ser.No. 10/400,100, filed Mar. 25, 2003, which claims the benefit of U.S.Provisional Patent Application No. 60/367,957, filed Mar. 26, 2002, thedisclosures of which applications are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to microparticles of drugs, especiallydrugs that are poorly soluble in water, and to methods for making them.

BACKGROUND OF THE INVENTION

Many important drugs have poor oral bioavailability because they arepoorly soluble in water. Many approaches have been suggested to overcomethis problem. Although some approaches have been used, with limitedcommercial success, each approach has its own drawbacks and limitations.

In one approach, a water-soluble prodrug of a poorly water-soluble drugis made [1-4]. The prodrug approach is limited to those molecules thathave functionality amenable to facile removal in the body to form thedrug. Not all poorly water-soluble drugs are so endowed. Furthermore,the prodrug would likely be considered a new chemical entity and requireseparate approval from regulatory agencies, adding considerable time andcost to bringing the product to market.

The bioavailability of poorly water-soluble drugs has been improved bydecreasing the particle size of the drug to increase the surface area.Milling [5-6], high pressure homogenization [7-8], spray drying [9],lyophilization of solutions in water organic solvent mixtures [10], andlyophilization of solutions inorganic solvents [11-12] have been tried.Size reduction is, in principal, generally applicable for improvingbioavailability, but achieving size reduction by, for example, highenergy milling, requires special equipment and is not always applicable.High pressure homogenization requires special equipment and requiresorganic solvents that can remain in the comminuted product. Spray dryingalso requires solvents and generally produces particles that are toolarge.

Lyophilization is usually limited to materials that are soluble in waterin any event, although there have been some efforts at using organicsolvents.

The solubility of poorly soluble antibiotics has been improved bycomplexation with polymers or cyclodextrins. Polymer complexes have beenformed with PVP in organic solvent [13a], or with PVP in heated water[13]. Other drugs have been complexed with cyclodextrins and polymers[14-15].

The bioavailability of poorly soluble drugs has been improved bydispersing the drug in a soluble polymer, often with addition ofsurfactants [16-24].

Some combinations of techniques have shown added improvement. Forexample spraying and drying a dispersion of drug and polymer orcyclodextrin on pellets in a fluidized bed dried [25-26]. Thecombination of solid dispersion and lyophilization to improve solubilityhas been demonstrated [27], and the use of solid dispersions absorbed ona carrier having a large surface area has also been demonstrated [28].

Clearly, there is a need for a simpler and generally applicable means ofmaking and delivering particles of drugs having a size below 10 μm andespecially below 1 μm.

Many of the above-described techniques require forming particles bysolvent removal which, in turn, entails concentration of a solution.During solution concentration, solute molecules, which in solution arestatistically separated into individual molecules and small clusters oraggregates, are drawn together to form larger molecular aggregates. Whenthe solute drug eventually precipitates, relatively larger crystals areformed.

Lyophilization (freeze drying) has the advantage of allowing the solventto be removed whilst keeping the solute relatively immobile, therebysuppressing enlargement of clusters or aggregates. When the solvent isremoved, the formed crystals are smaller or the material is amorphous,reflecting the separation of the molecules in the frozen solution state.Molecular separation can be improved and aggregate formation stillfurther suppressed by lyophilizing a more dilute solution, although onepays a hefty price in energy requirements for removing more solvent.Lyophilization is usually a very slow, energy intensive process andusually requires high vacuum equipment. Furthermore, there is a tendencyfor the crystals formed to aggregate in the free state, undoing the jobthat the freeze drying did. This tendency can sometimes be overcome withadditives, but these must be compatible with the entire system.

Amorphous or nanoparticulate materials tend to show poor bulk flowproperties as powders, requiring formulation work to be able to fillthem into capsules. While these problems are not insurmountable, theyadd further limitations in the usefulness of the system. Many of theexisting limitations are overcome by the present invention.

SUMMARY OF THE INVENTION

The present invention relates to a drug delivery vehicle including apharmaceutical carrier particle, especially a pharmaceutical carrierparticle that is a sugar particle, a starch particle, a lactoseparticle, or a particle of microcrystalline cellulose, bearingmicroparticles of a drug, especially a drug having poor solubility inwater, wherein the microparticles of the drug are deposited on thepharmaceutical carrier particle from a solid solution of the drug in asublimable carrier such as menthol, thymol, camphor, t-butanol,trichloro-t-butanol, imidazole, coumarin, acetic acid (glacial),dimethylsulfone, urea, vanillin, camphene, salicylamide, and2-aminopyridine. The drug delivery vehicle of the present invention isuseful for delivering a drug, especially a drug that has poor solubilityin water, to a mammal, especially a human, in need of treatment withthat drug.

In another aspect, the present invention relates to a method of making amicroparticle including the steps of forming a solid solution of thedrug in a sublimable carrier and removing the sublimable carrier fromthe solid solution by, for example, sublimation. Sublimation can beaccomplished in a fluidized bed apparatus.

In another aspect, the present invention relates to a method of making adrug delivery vehicle including the steps of forming a solid solution ofthe drug and a sublimable carrier on the surface of a pharmaceuticalcarrier particle, especially a pharmaceutical carrier particle that is asugar particle, a starch particle, a lactose particle, or a particle ofmicrocrystalline cellulose, and removing the sublimable carrier from thesolid solution, for example by sublimation, to deposit microparticles ofthe drug on the pharmaceutical carrier particle. The solid solution canbe formed on the carrier particle by, for example, combining drug,sublimable carrier, and a solvent (for example ethanol), applying thecombination to the carrier particle, and removing the solvent. The solidsolution can also be formed by applying a combination of drug and moltensublimable carrier to the particle and allowing the combination to coolto form the solid solution on the carrier particle.

In yet another aspect, the present invention relates to pharmaceuticalcompositions that include microparticles of the present invention, whichmicroparticles can be born by a drug delivery vehicle of the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides microparticles of a pharmacologicallyactive substance, i.e. a drug, and a method for making them. Theinvention also provides a drug delivery vehicle for administering apharmacologically active substance, and methods for making it, whereinthe delivery vehicle includes at least one pharmaceutical carrierparticle bearing microparticles of the drug, which microparticles aremade according to the present invention.

Microparticles of the present invention are formed as describedhereinbelow and generally have mean dimensions on the order of about 100nm, up to about 10 μm. Microparticles according to the present inventioncan have a regular shape, e.g. essentially spherical, or they can havean irregular shape. The material of which microparticles are comprisedcan be crystalline or it can be at least partly amorphous. Preferablythe material is at least partly amorphous.

As used herein in connection with a measured quantity, the term aboutrefers to the normal variation in that measured quantity that would beexpected by the skilled artisan making the measurement and exercising alevel of care commensurate with the objective of the measurement and theprecision of the measuring equipment used.

Any pharmagologically active substance (drug) can be used in thepractice of the present invention. However, drugs having poor watersolubility (poorly water soluble drugs), and hence relatively lowerbioavailability, are preferred and the advantages of the presentinvention are more fully realized with poorly water-soluble drugs. Forpurposes of the present invention, a drug is considered to be poorlywater soluble if it has a solubility of less than about 20 mg/permilliliter of water. Examples of drugs having poor water solubilityinclude fenofibrate, itraconazole, bromocriptine, carbamazepine,diazepam, paclitaxel, etoposide, camptothecin, danazole, progesterone,nitrofurantoin, estradiol, estrone, oxfendazole, proquazone, ketoprofen,nifedipine, verapamil, and glyburide, to mention just a few. The skilledartisan knows other drugs having poor water solubility.

Pharmaceutical carrier particles useful for making the delivery vehicleof the present invention are made of comestible substances and are wellknown in the art. Examples of useful pharmaceutical carrier particlesinclude particles, that can be non-pariel pellets, typically betweenabout 0.1 mm. and about 2 mm. in diameter, and made of, for example,starch, particles of microcrystalline cellulose, lactose particles or,particularly, sugar particles. Suitable sugar particles (pellets, e.g.non-pariel 103, Nu-core, Nu-pariel) are commercially available in sizesfrom 35 to 40 mesh to 18 to 14 mesh. Particles of microcrystallinecellulose are preferred pharmaceutical carrier particles. The skilledartisan knows other pellets or spheres useful as pharmaceutical carrierparticles.

The microparticles of the drug or pharmacologically active substance ofthe present invention are obtained by removing a sublimable carrier froma solid solution of the drug in the sublimable carrier. The drug orpharamaceutically active substance can be present with the sublimablecarrier in the solid solution as discrete molecules, or it can bepresent in aggregates of a few hundred, a few thousand, or moremolecules. The drug need only be dispersed on a sufficiently small scaleso that sufficiently small, discrete microparticles are ultimatelyobtained. Preferably, the drug or pharmagolocigally active substance inthe solid solution is dissolved in the sublimable carrier.

Sublimable carriers useful in the practice of the present invention formsolid solutions with the drug at an easily accessible temperature andcan be removed from the solid solution without heating the solidsolution to a temperature above the melting point of the solid solution,for example by sublimation. Sublimable carriers have a measurable vaporpressure below their melting point. Preferred sublimable carriers have avapor pressure of at least about 10 Pascal, more preferably at leastabout 50 Pascal at about 10° or more below their normal melting points.Preferably, the sublimable carrier has a melting point between about−10° C. and about 200° C., more preferably between about 20° C. andabout 60° C., most preferably between about 40° C. and about 50° C.Preferably, the sublimable carrier is a substance that is classified bythe United States Food and Drug Administration as generally recognizedas safe (i.e., GRAS). Examples of suitable sublimable carriers includementhol, thymol, camphor, t-butanol, trichloro-t-butanol, imidazole,coumarin, acetic acid (glacial), dimethylsulfone, urea, vanillin,camphene, salicylamide, and 2-aminopyridine. Menthol is a particularlypreferred sublimable carrier.

The solid solutions of the present invention can exist as a truehomogeneous crystalline phase of the interstitial or substitutionaltype, composed of distinct chemical species occupying the lattice pointsat random, or they can be a dispersion of discrete molecules oraggregates of molecules in the sublimable carrier.

The solid solutions can be made by combining a drug with moltensublimable carrier, then cooling the combination to below the meltingpoint of the solid solution. The solid solutions can also be formed bycombining drug and sublimable carrier in an organic solvent andevaporating the organic solvent to obtain a solid solution of drug insublimable carrier. Ethanol is an example of a preferred organic solventthat can be used in the practice of the present invention.

The solid solution can also include a compound or polymer that forms adispersion with the drug.

In a preferred embodiment, the solid solution is formed on the surfaceof at least one pharmaceutical carrier particle and preferably aplurality of pharmaceutical carrier particles. For example, a moltencombination of drug and carrier can be applied to the surface of apharmaceutical carrier particle where it is allowed to cool to form thesolid solution on the surface of the pharmaceutical carrier particle. Asolid solution can also be formed at the surface of a pharmaceuticalcarrier particle by applying a combination of solvent, drug, andsublimable carrier to at least one, and preferably a plurality of,pharmaceutical carrier particle(s) and evaporating the organic solventto obtain the solid solution on the surface of the pharmaceuticalcarrier particle.

Application to the pharmaceutical carrier particles can be by anyparticle coating technique known in the art, for example using fluidizedbed equipment or a spray coater. When used, organic solvent is removedafter application by exposing the coated carrier particles to vacuum ora stream of heated or non-heated air using particle handling equipmentwell known in the art.

When no solvent is used, application is at a temperature above themelting point of the sublimable carrier. When drug and sublimablecarrier are combined with solvent, application is at a temperature suchthat drug and sublimable carrier remain in solution in the solvent.

The microparticles of the present invention are formed by removal ofsublimable carrier from a solid solution, made as described above, at atemperature below the melting point of the solid solution. The solidsolution must be kept at a temperature below its melting point topreserve the solid solution during the process of removing thesublimable carrier. The sublimable carrier can be removed from the solidsolution by, for example, treating the solid solution, deposited on apharmaceutical carrier particle where applicable, in a stream of air,preferably heated air, in, for example, a fluidized bed drier.

In those embodiments in which the solid solution is coated on thesurface of a pharmaceutical carrier particle, the sublimable carrier canbe removed by exposing the coated particles to heat, vacuum, heat andvacuum, or to a stream of heated or non-heated air, for example in afluidized bed dryer. Exposing coated pharmaceutical carrier particles toa stream of air (heated or not) in a fluidized bed dryer is a preferredmeans of removing sublimable carrier from solid solution coated onpharmaceutical carrier particles in order to form the microparticles ofthe present invention on the surface of the carrier particles.

Removal of sublimable carrier from the solid solution, whether coated ona pharmaceutical carrier particle or not, results in formation of themicroparticles of the present invention.

In another embodiment of the present invention, the microparticles ofdrug or the pharmaceutical carrier particles bearing microparticles of adrug are formulated into pharmaceutical compositions that can be madeinto dosage forms, in particular oral solid dosage forms such ascapsules and compressed tablets, as are well known in the art.

Compressed tablets are formulated from pharmaceutical compositionscontaining the microparticles of the pharmacologically active substanceor drug, or using pharmaceutical carrier particles bearing suchmicroparticles, and pharmacologically inert (pharmaceuticallyacceptable) additives or excipients.

For making a tablet, it will typically be desirable to include one ormore benign pharmaceutical excipients in the pharmaceutical composition.The pharmaceutical composition of the present invention may contain oneor more diluents added to make the tablet larger and, hence, easier forthe patient and caregiver to handle. Common diluents aremicrocrystalline cellulose (e.g. Avicel®), microfine cellulose, lactose,starch, pregelitinized starch, calcium carbonate, calcium sulfate,sugar, dextrates, dextrin, dextrose, dibasic calcium phosphatedihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate,magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g.Eudragit®), potassium chloride, powdered cellulose, sodium chloride,sorbitol and talc.

Binders also may be included in tablet formulations to help hold thetablet together after compression. Some typical binders are acacia,alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium,dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil,hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®),hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose,magnesium aluminum silicate, maltodextrin, methylcellulose,polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinizedstarch, sodium alginate and starch.

The tablet may further include a disintegrant to acceleratedisintegration of the tablet in the patient's stomach. Disintegrantsinclude alginic acid, carboxymethyl cellulose calcium,carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellosesodium (e.g. Ac-Di-Sol®, Primellose®), crospovidone (e.g. Kollidon®,Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose,microcrystalline cellulose, polacrilin potassium, powdered cellulose,pregelatinized starch, sodium alginate, sodium starch glycolate (e.g.Explotab®) and starch.

A pharmaceutical composition for making compressed tablets may furtherinclude glidants, lubricants, flavorings, colorants and other commonlyused excipients.

Pharmaceutical carrier particles bearing microparticles of a drug madein accordance with the present invention have excellent bulk flowproperties and can be used directly, alone or in combination withcarrier particles that do not carry a drug, to make capsule dosageforms. If necessary, diluents such as lactose, mannitol, calciumcarbonate, and magnesium carbonate, to mention just a few, can beformulated with the microparticle-bearing pharmaceutical carrierparticles when making capsules

Liquid oral pharmaceutical compositions of the present inventioncomprise microparticles or microparticle-bearing pharmaceutical carrierparticles and a liquid carrier such as water, vegetable oil, alcohol,polyethylene glycol, propylene glycol or glycerin, most preferablywater.

Liquid oral pharmaceutical compositions may contain emulsifying agentsto disperse uniformly throughout the composition the active ingredient,drug delivery vehicle, or excipient having low solubility in the liquidcarrier. Emulsifying agents that may be useful in liquid compositions ofthe present invention include, for example, gelatin, egg yolk, casein,cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose,carbomer, cetostearyl alcohol and cetyl alcohol.

Liquid oral pharmaceutical compositions of the present invention mayalso contain a viscosity enhancing agent to improve the mouth-feel ofthe product and/or coat the lining of the gastrointestinal tract. Suchagents include acacia, alginic acid bentonite, carbomer,carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin,polyvinyl alcohol, povidone, propylene carbonate, propylene glycolalginate, sodium alginate, sodium starch glycolate, starch tragacanthand xanthan gum.

The liquid oral pharmaceutical composition also may contain sweeteningagents, such as sorbitol, saccharin, sodium saccharin, sucrose,aspartame, fructose, mannitol and invert sugar; preservatives andchelating agents such as alcohol, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid;and buffers such as guconic acid, lactic acid, citric acid or aceticacid, sodium gluconate, sodium lactate, sodium citrate or sodiumacetate.

The present invention is further illustrated with the followingexamples.

Example 1 Solubility of Selected Drugs in Menthol

The following general procedure was repeated with several drugs withmenthol carrier.

Menthol (10 grams) was melted on a stirring hot plate with magneticstirring, then heated to the desired temperature indicated in Table 1.The desired drug was added in small increments (0.1 grams) and stirredto obtain a clear solution. The desired drug was added in incrementsuntil no more drug dissolved in the menthol. The weight of materialadded to the menthol melt that still gave a clear solution was taken asthe solubility of the active drug at the indicated temperature. Theresults are given in Table 1.

TABLE 1 Solubility of selected active drug substances in mentholtemperature Solubility Active drug substance (° C.) (% w/w) Azithromycin63 40.0 Cyclosporin 55 39.2 Diazepam 43 5.7 Fenofibrate 60 37.5Itraconazole 61 1.0 Oxybutynin 60 9.1 Risperidone 70 8.3 Salicylic acid43 16.0 Simvastatin 63 30.0

Example 2 Improvement of the Dissolution of Fenofibrate by “MentholMicronization”

Menthol (50 grams) was heated in a jacketed reactor to 60° C. Aftermelting, the melt was stirred at 100 rpm. Fenofibrate (25 grams) wasadded and the mixture stirred at 100 rpm and 60° C. until fulldissolution was achieved. Microcrystalline cellulose (Avicel ph 102, 55grams) was added to the melt and the mixture was stirred for 30 minutes.The heat source was then removed and the mass allowed to cool to roomtemperature with the stirring continued at 100 rpm for a further 30minutes.

The obtained mass was milled through a 6.35 mm screen in a Quadra Comilmill at 1300 rpm. The milled product was allowed to cool to 25° C. andmilled again through 1.4 mm screen to obtain a powder in which thefenofibrate is dissolved in menthol and coated on the microcrystallinecellulose.

The powder was transferred to a fluid bed dryer (Aeromatic model STREA1)where the menthol was removed by drying for three hours at 30-32° C.with the fan at 7-8 Nm³/hr. A powder, 62 grams, was obtained. Thispowder was an essentially “micronized” fenofibrate deposited onmicrocrystalline cellulose.

A sample of this powder containing 100 mg of the fenofibrate was testedfor dissolution in a USP Apparatus II dissolution tester in 900 ml 0.5%sodium lauryl sulfate (SLS) in water at 37° C. and 100 rpm. Thefenofibrate in the dissolution medium was determined by HPLC on anHypersil® ODS column with UV detection at 286 nm. The results are shownin Table 2. Fenofibrate “micronized” by the menthol method gave 100%dissolution in two hours. An equivalent simple combination offenofibrate (control, not deposited from menthol) with microcrystallinecellulose gave 40.2% dissolution in 3 hours, while a mechanicallymicronized fenofibrate raw material mixed with microcrystallinecellulose gave 72.1% dissolution in 3 hours.

TABLE 2 Dissolution of menthol treated fenofibrate time (minutes) %dissolved 15 44.0 +/− 1.3 30 73.6 +/− 2.9 60 82.3 +/− 0.6 90 93.1 +/−4.2 120 102.7 +/− 0.2  180 104.9 +/− 0.8 

Example 3 Improvement of the Dissolution of Oxybutynin Chloride by“Menthol Micronization”

Menthol (80 grams) was melted and oxybutynin chloride (8 grams) andmicrocrystalline cellulose (89.5 grams) were added and treated as inExample 2 to give a powder of “micronized” oxybutynin chloride onmicrocrystalline cellulose.

The dissolution of oxybutynin chloride from this powder (a sample ofpowder containing 100 mg of the active drug) was tested in a USPapparatus II dissolution tester in 100 ml of 50 mM phosphate bufferpH=6.8 at 37° C. and 50 rpm. The oxybutynin content of the dissolutionsample was measured by spectrophotometer at 225 tun. The results aregiven in Table 3. The dissolution reached 79.2% at three hours. Anequivalent simple combination of the oxybutynin chloride raw materialwith microcrystalline cellulose that was not treated with the “mentholmicronization” method gave only 22.1% dissolution in three hours.

TABLE 3 Dissolution of menthol treated oxybutynin time (minutes) %dissolved 30 21.5 +/− 0.4 90 59.7 +/− 1.2 180 79.2 +/− 1.0

Example 4 Improvement of the Dissolution of Risperidone by “MentholMicronization”

Menthol (50 grams) was melted and risperidone (4.5 grams) andmicrocrystalline cellulose (62.5 grams) were added and treated accordingto the procedure in Example 2. A sample of the resulting powder(containing 50 mg of risperidone) was tested in a USP apparatus IIdissolution tester using 900 ml of water at 37° C. and 100 rpm. Theconcentration of risperidone in the dissolution samples was measuredusing a spectrophotometer at 240 nm.

The results of the dissolution of the “menthol micronized” powder and ofthe control simple combination of risperidone and microcrystallinecellulose (not treated with menthol) are shown in Table 4. The mentholdeposited risperidone gave 100% dissolution in 30 minutes, whereas thecontrol mixture gave 31.9% in thirty minutes and 63.7% in three hours.

TABLE 4 Dissolution of menthol treated risperidone vs. control time(minutes) % dissolved test % dissolved control 15  69.3 +/− 0.5 17.5 +/−2.6 30  99.9 +/− 1.0 31.9 +/− 3.5 60 102.3 +/− 0.8 41.7 +/− 5.6 90 102.8+/− 1.2 48.2 +/− 8.3 120  53.2 +/− 11.1 180 63.7 +/− 8.3

Example 5 Improvement of the Dissolution of Cyclosporin by “MentholMicronization”

Menthol (80 grams) was melted and cyclosporin (20 grams) andmicrocrystalline cellulose (100 grams) were added and treated as inExample 2. A sample of this powder (containing 10 mg of “mentholmicronized” cyclosporin) was tested for dissolution in 900 ml water in aUSP apparatus II dissolution unit at 37° C. and 100 rpm. The cyclosporincontent of the dissolution samples was determined spectrophotometricallyat 215 nm. The dissolution of the menthol deposited material and of acontrol mixture of cyclosporin and microcrystalline cellulose (notdeposited from menthol) are presented in Table 5. The cyclosporindissolution from the powder having cyclosporin deposited from mentholwas about twice that of the control (simple combination), and themaximum dissolution was achieved in shorter time.

TABLE 5 Dissolution of menthol treated cyclosporin vs. control time(minutes) % dissolved test % dissolved control 30  9.2 +/− 0.3 0.1 +/−0.0 60 11.9 +/− 0.3 1.3 +/− 0.5 90 13.1 +/− 0.5 3.1 +/− 0.2 120 13.3 +/−0.3 5.1 +/− 0.2 180 14.3 +/− 0.8 7.1 +/− 0.3

Example 6 Comparative—Attempted Improvement in Itraconazole Dissolutionby “Menthol Micronization”

Menthol (92 grams) was melted as in Example 2. Itraconazole (3.6 grams)was added and mixed well in the melt. A solution was not formed becauseitraconazole has a solubility of only 1% in menthol at 60° C. (see Table1). To the suspension of itraconazole in menthol was addedmicrocrystalline cellulose (90 grams) and the mixture treated as inExample 2. The dissolution of the itraconazole was measured from apowder sample containing 100 mg of the drug in 900 ml of 0.1N HCl in aUSP apparatus II dissolution tester at 37° C. and 100 rpm. The dissolveditraconazole was measured spectrophotometrically at 251 nm. The resultsof the dissolution are shown in Table 6. The dissolution was about 8% at30 minutes and the same at three hours. A control simple mixture ofitraconazole and microcrystalline cellulose (not deposited from menthol)gave essentially the same results (7.8% in three hours).

TABLE 6 Dissolution of menthol treated itraconazole time (minutes) %dissolved 30 8.8 +/− 0.4 90 8.0 +/− 0.6 180 8.1 +/− 0.1

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1. A drug delivery vehicle comprising at least one pharmaceuticalcarrier particle bearing on its surface microparticles of a poorly watersoluble drug, wherein the microparticles have a mean particle size ofabout 100 nm to about 10 μm with the proviso that the poorly watersoluble drug is not fenofibrate.
 2. The drug delivery vehicle of claim1, wherein the poorly water soluble drug is selected from the groupconsisting of itraconazole, bromocriptine, carbamazepine, diazepam,paclitaxel, etoposide, camptothecin, danazole, progesterone,nitrofurantoin, estradiol, estrone, oxfendazole, proquazone, ketoprofen,nifedipine, verapamil, and glyburide.
 3. The drug delivery vehicle ofclaim 2 wherein the pharmaceutical carrier particle comprises at leastone pharmaceutical particle selected from the group consisting of starchparticles, microcrystalline starch particles, microcrystalline celluloseparticles, lactose particles, and sugar particles.
 4. The drug deliveryvehicle of claim 3 wherein the pharmaceutical carrier particle comprisesparticles of microcrystalline cellulose.
 5. A method of making the drugdelivery vehicle of claim 1, comprising the steps of: a) forming a solidsolution comprising the drug and a sublimable carrier on the surface ofa pharmaceutical carrier particle, and b) subliming the sublimablecarrier from the solid solution to deposit microparticles of the drug onthe surface of the pharmaceutical carrier particle to obtain the drugdelivery vehicle.
 6. The method of claim 5 wherein the solid solution isformed by combining the drug with molten sublimable carrier, applyingthe combination to at least one pharmaceutical carrier particle, andthereafter allowing the combination to solidify to obtain the solidsolution on the surface of the pharmaceutical carrier particle.
 7. Themethod of claim 5 wherein the solid solution is formed by combining thedrug and the sublimable carrier with an organic solvent, applying thecombination to at least one pharmaceutical carrier particle, andevaporating the organic solvent to obtain the solid solution on thesurface of the at least one pharmaceutical carrier particle.
 8. Themethod of claim 7 wherein the solvent is ethanol.
 9. The method of claim5 wherein the sublimable carrier is selected from the group consistingof menthol, thymol, camphor, t-butanol, trichloro-t-butanol, imidazole,coumarin, acetic acid (glacial), dimethylsulfone, urea, vanillin,camphene, salicylamide, and 2-aminopyridine.
 10. The method of claim 5wherein the pharmaceutical carrier particle is selected from the groupconsisting of starch particles, sugar particles, lactose particles,particles of microcrystalline cellulose, and mixtures of any of these.11. The method of claim 5 wherein the drug is selected from the groupconsisting of itraconazole, bromocriptine, carbamazepine, diazepam,paclitaxel, etoposide, camptothecin, danazole, progesterone,nitrofurantoin, estradiol, estrone, oxfendazole, proquazone, ketoprofen,nifedipine, verapamil, and glyburide.
 12. A pharmaceutical compositioncomprising at least one pharmaceutically acceptable excipient and thedrug delivery vehicle of claim
 1. 13. An oral solid dosage formcomprising a pharmaceutical composition according to claim
 12. 14. Thedrug delivery vehicle of claim 1 wherein the ratio of carrier particlesto drug is about 2:1 to about 14:1
 15. The drug delivery vehicle ofclaim 14, wherein the microparticles are obtained without mechanicalmicronization.